Linked Life Data

17698617

Source:http://linkedlifedata.com/resource/pubmed/id/17698617

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2008-1-1
pubmed:abstractText
Multiple studies have addressed the mechanisms by which ultraviolet (UV) light induces cell death, and a few have focused on stress mediators such as acid sphingomyelinase (ASMase) or protein kinase Cdelta (PKCdelta). Based on a recent study that identified a novel mechanism of activation of ASMase through phosphorylation, the current study was undertaken to determine the upstream mechanisms regulating ASMase in response to UV and to investigate the role of ASMase and its phosphorylation at S508 as an integral event during UV light-induced cell death. Exposure of MCF-7 breast cancer cells to UV light type C (UVC) transiently activated ASMase with maximal activity detected at 10 min postirradiation. A significant increase in C16-ceramide was detected concomitant with a decrease in C16-sphingomyelin. In marked contrast, cells overexpressing the ASMase(S508A) mutant, which could not be phosphorylated, had no change in either ASMase activity or ceramide levels post-UV radiation. Loss of PKCdelta by RNA interference or its inhibition by rottlerin blocked ASMase phosphorylation and membrane targeting, thus implicating PKCdelta upstream of ASMase activation by UV light. Further investigations revealed that UV radiation altered mitochondrial morphology from elongated tubules to fragmented perinuclear organelles, consistent with the onset of the apoptotic cascade. Importantly, cells overexpressing ASMase(S508A) were protected (>50%) from UV light-induced mitochondrial fragmentation. Mechanistically, the results showed that ASMase(S508A) cells had 50% less active Bax than ASMase(WT) cells. These molecular differences culminated in resistance of ASMase(S508) cells to UVC-induced cell death (25%) as compared to ASMase(WT) cells (46%). Taken together, this study provides key molecular insights into activation of ASMase in response to UV light, the role of PKCdelta in this activation, and the role of ASMase in mediating apoptotic responses.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
1530-6860
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
22
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
183-93
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed:year
2008
pubmed:articleTitle
A novel role for protein kinase Cdelta-mediated phosphorylation of acid sphingomyelinase in UV light-induced mitochondrial injury.
pubmed:affiliation
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural